Kaposi's sarcoma (KS), an AIDS-defining malignancy, is always associated with Kaposi's sarcoma herpesvirus infection (KSHV or HHV-8). Chemotherapy gives approximately a 50% response rate. Radiation plays only a palliative role in the management of KS because it is disseminated. We propose a novel approach to delivering targeted radiation to disseminated KS. The approach involves trapping a nucleoside analog (FIAU) in KSHV-infected cells (FIAU retention). The virus encodes a thymidine kinase (TK) that will selectively phosphorylate FIAU. The viral TK is only likely to be expressed in a minority of cells in KS. However, in preclinical models bortezomib is a potent inducer of KSHV TK, and phosphorylation results in trapping radiolabeled FIAU in cells allowing tumor imaging and therapy. Cutaneous involvement with AIDS-related KS presents the unique opportunity to assess directly the radiation concentration and the expression of viral RNA and viral antigens in tumor tissue. We propose to evaluate bortezomib-induced enzyme targeted radiation (BETR) therapy in patients with AIDS-related KS. The possibility of having readily available biopsy specimens with which to work, which is somewhat unique to this malignancy, provides a rare opportunity to correlate imaging findings directly with changes in viral expression in tumor tissue in human subjects. We propose a trial to evaluate targeting of FIAU to KS in a dose-response study with bortezomib, to evaluate the safety and toxicity of fixed-dose [1311JF1AU in combination with bortezomib, to describe biopsy correlates of [1241JF1AU retention, and to characterize the objective response to the therapy with [131] FIAU. Because we believe that the doses of bortezomib approved for use as single agent therapy in the treatment of multiple myeloma are likely to be higher than are needed for imaging, our trial begins with lower doses and escalates to the standard clinical dose.